The long-term objective of this project is to establish an innovative therapeutic approach toward glucocorticoid-induced osteonecrosis of the femoral head (ONFH), using nano-fullerenes which function as outstanding reactive oxygen species (ROS) scavengers. Glucocorticoid administration for treatment of various inflammatory and autoimmune diseases is the most common non-traumatic cause of ONFH. ONFH is a debilitating disease affecting young adults from the third decade of life. Consequently most patients often need multiple increasingly difficult surgeries over the course of their lifetime. Successful treatment of ONFH still remains a big challenge to both scientists and clinicians, due to the difficulties in its early diagnose, the complexity in its etiology and the limited knowledgein its pathogenesis. The hypothesis is that nano-fullerenes might be very effective in treatment of ONFH, and a polyhydroxylated fullerene fullerol with better solubility might elicit a greater activity than the pristine C60. The following specific aims are included: 1. To determine the antagonizing activity of nano-fullerenes against dexamethasone (DEX)- induced adipogenesis and apoptosis in rabbit bone marrow stromal cells in vitro. 2. To evaluate in vivo preventive effects of nano-fullerenes on the development of osteonecrosis of the femoral head (ONFH) in a rabbit model. Aqueous nanoparticle suspension will be prepared from the pristine C60 and fullerol. These two nano-fullerenes and glutathione will be administered and their effectiveness in prevention and treatment of ONFH will be determined in vitro in cell culture and in vivo in an animal model. Various experimental approaches such as histology, real-time PCR, western blot, flow cytometry, blood biochemistry, femur histopathology and single photon emission computed tomography (SPECT) will be employed. It is expected that all three antioxidants can inhibit ONFH development but the activity of fullerol is the strongest. These outcomes would support an innovative concept that nano-fullerenes can effectively treat glucocorticoid-induced ONFH. The study will provide scientific basis for a new therapeutic strategy and lead to novel development of pharmaceutical drugs for ONFH treatment.